This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height O2 S.D. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were R10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (rZ0.23, PZ0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 -X-linked acrogigantism (X-LAG) -occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in O50% of cases.

Objective: Disorders caused by impairments in the parathyroid hormone (PTH) signalling pathway are historically classified under the term pseudohypoparathyroidism (PHP), which encompasses rare, related and highly heterogeneous diseases with demonstrated (epi)genetic causes. The actual classification is based on the presence or absence of specific clinical and biochemical signs together with an in vivo response to exogenous PTH and the results of an in vitro assay to measure Gsa protein activity. However, this classification disregards other related diseases such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH), as well as recent findings of clinical and genetic/epigenetic background of the different subtypes. Therefore, the EuroPHP network decided to develop a new classification that encompasses all disorders with impairments in PTH and/or PTHrP cAMP-mediated pathway. Design and methods: Extensive review of the literature was performed. Several meetings were organised to discuss about a new, more effective and accurate way to describe disorders caused by abnormalities of the PTH/PTHrP signalling pathway. Results and conclusions: After determining the major and minor criteria to be considered for the diagnosis of these disorders, we proposed to group them under the term 'inactivating PTH/PTHrP signalling disorder' (iPPSD). This terminology: (i) defines the common mechanism responsible for all diseases; (ii) does not require a confirmed genetic defect; (iii) avoids ambiguous terms like 'pseudo' and (iv) eliminates the clinical or molecular overlap

We review the three genetically determined disorders of glucose transport across cell membranes. Diseases such as glucose-galactose malabsorption, Fanconi-Bickel syndrome and De Vivo disease (GLUT1 deficiency syndrome (GLUT1DS)) arise from heritable mutations in transporter-encoding genes that impair monosaccharide uptake, which becomes rate-limiting in tissues where the transporters serve as the main glucose carrier systems. We focus in greater detail on De Vivo disease as a prototype of a brain energy failure syndrome, for which the greatest pathophysiological detail is known, but which presents the most therapeutic challenges. The study of these diseases illustrates fundamental aspects of energetic metabolism, while providing the basis for their diagnosis by simple metabolic screening and for their treatment by dietary modification.European Journal of Endocrinology 150 627-633

This first global review of PHP in Spain highlights the importance of a detailed clinical and genetic study of each patient and the integrated analysis of the findings from the two approaches. It may also help geneticists and clinicians to raise the suspicion of PHP earlier, reach more accurate diagnoses, and provide patients with PHP and their families with useful genetic information and counseling, thereby improving outcomes and quality of life.

Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and readyto-use tool to help physicians and patients outlining relevant interventions and their timing. A lifelong coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.

. Body cell mass: model development and validation at the cellular level of body composition. Am J Physiol Endocrinol Metab 286: E123-E128, 2004. First published October 7, 2003 10.1152/ajpendo.00227.2003.-Existing models to estimate the metabolically active body cell mass (BCM) component in vivo remain incompletely developed. The classic Moore model is based on an assumed BCM potassium content of 120 mmol/kg. Our objectives were to develop an improved total body potassium (TBK)-independent BCM prediction model on the basis of an earlier model (Cohn SH, Vaswani AN, Yasumura S, Yuen K, and Ellis KJ. J Lab Clin Med 105: [305][306][307][308][309][310][311] 1985), to apply this improved model in subjects to explore the sex and age dependence of the TBK/BCM ratio, to develop a new TBK/BCM model on the basis of physiological associations between TBK and total body water (TBW) at the cellular level of body composition, and to fit this new model with available reference data. Subjects were 112 healthy adults who had the following components measured: TBW by 2 H2O or 3 H2O, extracellular water by NaBr, total body nitrogen by in vivo neutron activation, bone mineral by dual-energy X-ray absorptiometry, and TBK by whole body counting. Human reference data were collected from earlier published reports. The improved Cohn model-derived TBK/BCM ratio was (mean Ϯ SD) 109.0 Ϯ 10.9 mmol/kg and was not significantly related to sex and age. A simplified version of the new TBK-TBW model provided a TBK/BCM ratio almost identical (109.1 mmol/kg) to that derived by the improved Cohn model. The TBK-BCM prediction formula derived from the improved and new models [BCM (kg) ϭ 1/109 ϫ TBK (mmol); or BCM ϭ 0.0092 ϫ TBK] gives BCM estimates ϳ11% higher than the classic Moore model (BCM ϭ 0.0083 ϫ TBK) formulated on rough tissue composition estimates. The present analyses provide a physiologically based, improved, and validated TBK-BCM prediction formula that should prove useful in body composition and metabolism research. total body potassium; nutritional assessment THE CONCEPT OF BODY CELL MASS (BCM), as proposed in 1963 by Moore et al. (15), reflects the cellular components of the body involved in biochemical processes and energy metabolism. BCM consists of the nonfat cellular portion of tissues, such as skeletal muscle, viscera, organs, blood, and brain. Nutritional status, physical activity level, and disease states alter BCM, which in turn serves as a biomarker of these processes (3, 7). Moore et al. (15) developed a BCM estimation formula of the general typewhere K e is total body exchangeable potassium measured by 42 K, and k (in kg/mmol) is the reciprocal of the potassium content of BCM. This model assumes that there is negligible extracellular fluid (ECF) potassium, all exchangeable potassium is within cells, and that the average cell potassium content is constant. Moore et al. then used available data to fit their model: an average nitrogen (N) content of BCM (i.e., 0.04 g N per g BCM) and an average K-to-N ratio of 3 mmol/g. A BCM...

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